Lloyd E. King

Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trélat, and multiple acrochordons. A possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes

CARCINOMAS have been associated with such paraneoplastic syndromes as skin-tumor growth, ectopic hormone production, arthropathies, myopathies, neuropathies, multiple thromboses, nephrosis, cachexi...

Localization of immunoreactive epidermal growth factor receptors in human nervous system.

Epidermal growth factor is a well-defined peptide which stimulates cell growth and elicits cell responses in a variety of tissues by binding to specific receptors, EGF-R. A specific antiserum against the EGF receptor, which has previously been used to characterize EGF-R in human skin, fibroblasts, and smooth muscle, was used to survey the distribution of EGF-R in human nervous system. Portions of formalin-fixed, paraffin-embedded autopsy specimens were examined by use of immunohistochemical staining (PAP technique) with EGF-R antiserum. Many types of nerve cells, e.g., cerebral cortical pyramidal cells, hippocampal pyramidal cells, Purkinje cells, anterior horn cells, and dorsal root ganglion neurons, contained immunoreactive EGF-R. However, immunoreactive EGF-R were not detected in astrocytes, oligodendrogliocytes, and other small neurons such as granule cells. Intense immunostaining for EGF-R was also detected in ependymal cells from choroidal and extrachoroidal locations. Although immunoreactive EGF-R is widely distributed in human nervous system, the functional role of EGF and its receptor in the nervous system remains unknown.

A Protective Role for Matrix Metalloproteinase-3 in Squamous Cell Carcinoma

Elevated expression of matrix metalloproteinase-3 (MMP-3/stromelysin-1) is associated with a variety of tumor types, although its in vivo functional role remains unclear. In human and murine squamous cell carcinoma (SCC), MMP-3 is expressed in the stromal compartment at all of the stages of tumor progression and is expressed by the malignant epithelial cells in late-stage, highly invasive tumors. To elucidate whether MMP-3 plays a causal role during SCC, wild-type and MMP-3 null mice were subjected to chemical carcinogenesis procedures by topical application of either the complete carcinogen 1-methyl-3-nitro-1-nitroso-guanidine or two-stage initiation and promotion with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Contrasting with our expectations, tumors originating on MMP-3 null mice had enhanced initial tumor growth rates as compared with control animals, although there was no difference in tumor onset or incidence. This elevated rate in growth was coupled with an elevated proliferative index and a reduced vasculature density but with no significant effect on apoptosis. Tumors from MMP-3 null mice had a prevalence of undifferentiated spindle tumors as compared with controls, which was concomitant with a higher percentage of MMP-3 null mice evidencing surface lung metastases. Tumor progression in MMP-3 null mice was inversely associated with leukocyte infiltration, in which an overall reduction in tumor-associated macrophages and neutrophils was evident. We propose that MMP-3 is expressed as a protective response and plays an important role in host defense during SCC tumorigenesis.

Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy

BACKGROUND Few studies have assessed the long-term outcome of patients with cutaneous T-cell lymphoma (CTCL) treated with extracorporeal photochemotherapy (ECP). OBJECTIVE Our objective was to assess the efficacy, safety, and survival of a cohort of patients with refractory T-cell lymphoma in various stages of cutaneous involvement who were treated with ECP. METHODS Twenty patients who had received at least 6 months of ECP between September 1988 and April 1991 were reevaluated and the data analyzed statistically to obtain outcome data through December 1995. RESULTS A complete response (disappearance of all lesions) was obtained in five patients (25%) and a partial response (disappearance of at least 50% of lesions) in five patients (25%). Of the 10 responders, seven (70%) were weaned from ECP. Two of seven patients had a relapse. Ten patients (50%) showed no response to ECP. No statistically significant differences between responders and nonresponders were found with respect to demographic, clinical, or laboratory variables. Seven patients died of causes directly related to CTCL and two patients died of unrelated causes. Median survival time for the entire cohort was 96 months (range, 16 to 152 months). An assessment of early response after 6 to 8 months of ECP had a sensitivity of 100% and a specificity of 90% for predicting long-term (> 4 years) outcome. Adverse effects were minimal. CONCLUSION ECP is a safe effective alternative therapy for CTCL that is refractory to other therapies; it can induce a long-term, disease-free remission in a minority of patients. Response in the first 6 to 8 months of treatment predicts long-term outcome.

Brown recluse spider bites. A comparison of early surgical excision versus dapsone and delayed surgical excision.

In a prospective study, 31 patients with brown recluse spider bites were treated by either immediate surgical excision or with the leukocyte inhibitor, dapsone, followed by delayed surgical excision. Patients were matched for age, gender, and lesion size and were excluded if the typical history and physical findings were not present. In patients treated with immediate surgical excision (N = 14), delayed wound healing (N = 5) and objectional scarring (N = 7) were common complications. However, pretreatment treatment with dapsone reduced the incidence of wound complications (N = 1) and objectional scarring (N = 1) (p less than 0.05), while reducing the need for surgical excision (N = 1). There were no severe drug reactions due to dapsone, although one patient had persistent G.I. upset. Pretreatment with dapsone not only reduced surgical complications but also improved the outcome of patients bitten by the brown recluse spider.

Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma

BACKGROUND Many regimens are used for cutaneous T-cell lymphoma (CTCL), but with advanced disease response rates and patient survival are not adequate with any current therapy. Recently extracorporeal photochemotherapy (ECP) was proposed as an alternative therapy. OBJECTIVE Our purpose is to present the results of ECP in patients with CTCL refractory to other treatments. METHODS Patients with CTCL received ECP at 3- to 5-week intervals for at least 6 months. All patients except one were in stage T2 (patch/plaque) or higher. Eight patients had extracutaneous disease involving lymph nodes (six patients), bone marrow (five), or Sézary cells (six). The interval between initial symptoms and diagnosis was 5.9 +/- 1.9 years (mean +/- standard error of the mean) and the interval between diagnosis and ECP was 2.2 +/- 0.4 years. RESULTS A complete response (disappearance of all lesions) was obtained in five patients (25%) and a partial response (disappearance of at least 50% of lesions) in six patients (30%). Four patients (20%) showed stabilization of their disease and five progressed (25%). The only variable that predicted responders versus nonresponders was the number of ECP sessions (p < 0.05 by multivariate logistic regression). In contrast, no separate beneficial effect of adjunctive chemotherapy (p > 0.5) or electron beam therapy (p > 0.1) was found. CONCLUSION Long-term ECP may be an effective alternative treatment for CTCL refractory to other therapies and is likely to be even more useful when combined with other modalities.

Immunoreactive Epidermal Growth Factor Receptors in Neuritic Plaques from Patients with Alzheimer's Disease

Alzheimers disease (AD) is characterized neuropathologically by the presence of neuritic plaques (NP) in cerebral cortex and hippocampus, as well as intraneuronal neurofibrillary tangles and granulovacuolar degeneration. The etiology of plaque formation has remained obscure, but morphologically NPare known to contain amyloid cores surrounded by astrocytes and degenerating neurons. Although growth factors are important in growth, differentiation and regrowth in response to injury, studies relating growth factors to ADhave been lacking. Epidermal growth factor (EGF) plays an important role outside the central nervous system (CNS) through interaction with its specific receptor, EGF-R. Using an antibody to EGF-R(threestep immunoperoxidase staining) in conjunction with fluorescence staining, we found that the majority of NPfrom patients with pathologically confirmed AD as well as those few NPin the normal aging brain showed intense EGF-Rimmunoreactivity. Specific staining was seen at the periphery of plaques but not in the central amyloid core. Tissue sections from ADcases were also reacted with antibodies to both glial fibrillary acidic protein (GFAP) and paired helical filaments (PHF) in an attempt to identify which component of the NPwas reactive for EGF-R.The antibody to PHFdensely stained the periphery of NP but not the central core in a majority of NP. The antibody to GFAPstained a few reactive astrocytes that bordered plaques in only a small proportion of all plaques present. We conclude that the neuron and its processes although not exclusively may be the site of EGF-Rimmunoreactivity. An EGF/EGF-Rsystem within the CNS may play an important part in scar formation in response to neuronal injury and death or it may function as a trophic factor important in axonal or dendritic sprouting. It is also possible that EGFcould serve as a neurotransmitter/neuromodulator in the CNS

The diagnosis and treatment of brown recluse spider bites

We reviewed our experience with 95 patients who carried the diagnosis of brown recluse spider bite between 1983 and 1986 and identified a reference group of 17 with confirmed bites. Eight men and seven women, average age 32 years, presented within 33 hours following the bites. The most common symptoms were pain, pruritus, malaise, chills, sweats, and rash. Patients were randomized into three treatment groups: dapsone, brown recluse spider antivenom, or combination therapy. All patients were treated with erythromycin. If two patients with very severe lesions were excluded, patients in all groups healed their wounds in an average of 20 days. A comparison of our treatment was attempted with all other bites previously confirmed in the literature, but historical data were incomplete and no conclusions could be drawn.

Alopecia areata: an autoimmune disease?

Abstract: A wide range of hypotheses such as focal infection, trophoneur‐ oses, and endocrine dysfunction, have been previously proposed to explain the pathogenesis of alopecia areata (AA). Currently, the most widely held belief is that AA is an autoimmune disease with cellular and/or humoral immunity directed against anagen hair follicle antigen(s). However, until recently evidence in support of an autoimmune mechanism of AA has been largely circumstantial. More fundamental evidence has recently been amassed in support of AA as an autoimmune disease by using animal models. These data include: 1) identification of cross‐species hair follicle specific IgG autoantibodies, 2) The ability to induce AA in an animal model with transfer of skin from affected to naive individuals, and 3) the induction of disease by transfer of lymphocytes to human skin grafted to severe combined immunodeficiency mutant mice. A review of the pre‐ vious and current data related to the autoimmune basis of AA is provided to put into perspective the future studies needed to definitively determine whether AA is an autoimmune disease.

Oestrogen receptor‐β expression in melanocytic lesions

Abstract:  Melanomas rarely occur before puberty, have a higher death rate for males, and tend to be more invasive during pregnancy. Prior to the discovery of a second oestrogen receptor (ERβ), studies with the initial oestrogen receptor, ERα, showed no obvious role for oestrogen in the pathophysiology of benign or malignant melanocytic lesions. To investigate the specific immunostaining patterns of ERα and ERβ, benign nevocytic nevi, dysplastic nevi with mild, moderate and severe cytological atypia, lentigo malignas and melanomas of varying depth (Clark) and thickness (Breslow) were studied. ERβ but not ERα was the predominant oestrogen receptor we found in all types of benign and malignant melanocytic lesions. The most intense ERβ immunostaining was seen in melanocytes in dysplastic nevi with severe cytological atypia and in lentigo malignas. ERβ expression levels also correlated with the malignant tumor microenvironment; i.e., melanocytes in proximity with keratinocytes>deeper dermal melanocytes in contact with stroma>minimally invasive melanomas>Clark Level III/IV or thick melanomas (Breslow). Discovery that ERβ expression varies in relation to the tumor microenvironment and increasing depth of invasion suggests its possible usefulness as a surrogate marker for neoplasia and prognosis in malignant melanoma.